The Peoples Republic of China has the second highest overall case burden of TB in the world (behind India). The WHO Global Tuberculosis Report 2012 estimated that, in 2011, China had 1,400,000 cases of TB, with a prevalence of 104/100,000 population and an incidence of 75/100,000 population. For MDR TB, China has the highest annual number of cases in the world. Among all new TB cases in 2011, an estimated 5.7% (49,000 people) were MDR-TB. Among retreated TB cases in 2011, an estimated 26% (12,000 people) were MDR. Ten percent of all new pulmonary TB cases in China each year occur in Henan Province and reported MDR TB rates in Henan are among the highest across the country. In partnership with provincial health authorities in Zhengzhou, the capital of Henan Province, the Tuberculosis Research Section is developing the sites capacity to conduct high-quality clinical research. In 2009, NIAID Deputy Director Hugh Auchincloss signed an Implementing Arrangement with the Henan Provincial Bureau of Health to establish a collaborative research center. In response the provincial government announced that they would construct a new provincial-level infectious diseases hospital to house the research facility and better accommodate the heavy burden of patients in Henan Province. A prospective, longitudinal natural history study entitled A Natural History Study of Tuberculosis in China: Correlates of a Successful Response in Treatment (NIAID 10-I-N060) was approved by the NIAID IRB and enrollment commenced after lab renovation and installation of equipment in March 2010. This protocol enrolled 150 subjects with suspected TB at the Henan Provincial Chest Hospital. The subjects were divided into three cohorts according to their diagnosis: A) Acid-fast bacilli (AFB) smear positive pulmonary tuberculosis, B) AFB smear negative pulmonary tuberculosis, and C) extra pulmonary tuberculosis (EPTB) and these subjects were actively followed for six months during their initial response to antituberculous chemotherapy, then passively followed for another year, with a phone call at the end of that year to determine TB cure vs. relapse status. Twenty-five (25) healthy controls (Cohort D) were also enrolled to determine baseline values for immunologic responses and laboratory values. This study will analyze changes in total volume of disease as assessed by quantitative CT scanning at baseline, 2, and 6 months. In addition, we will monitor chemotherapeutic regimens, changes in the host immune response, overall changes in clinical parameters, initial and acquired drug-resistance of the infecting isolates, and changes in bacterial and host markers in subject samples during chemotherapy. In each case, we will look for associations of these parameters with rates of disease resolution correlated with specific structural features determined by CT scanning at the site of TB disease. This study will allow us to evaluate eligibility criteria for future clinical trials, establish TB diagnostic accuracy, understand the local standard of care, initial anti-TB regimen selection and subsequent modifications, evaluate mycobacterial strain characteristics, extent of disease, types of lesions and host immunologic response to chemotherapy, as well as identify surrogate markers to monitor the response to chemotherapy. As of August 1, 2013, all 150 subjects were fully enrolled into the study with follow-up phone calls one year later (18 months after enrollment) to ascertain TB cure vs. relapse status also completed. Study personnel cultured bacteria from sputa and other samples, collected and froze plasma, performed gamma interferon stimulation assays, and completed case report forms on a regular basis. The OpenClinica database designed for the study is being used by the data entry personal, allowing us to monitor the progress of the study remotely. The study team is performing QuantiFERON (QFT) testing and two molecular tests for establishing drug resistance. The QFT test uses whole blood to detect interferon gamma production in response to mycobacterial antigens in serial samples collected prior to and during anti-tubercular treatment. We are also planning to assess the changes in cytokine and chemokine levels in the subjects sera during treatment in collaboration with Drs Kaplan and Sher. In addition, bacterial DNA was isolated from cultured sputa and/or sputum sediment and was used to detect rifampicin and isoniazid resistance (Hain test) and speciate non-tuberculous mycobacteria (NTM) (reverse line blot assay). Among the subject specimens tested thus far, 15% were determined to be multidrug resistant by culture, 4% had XDR TB and 4% contained predominantly NTM based on the Reba results. Two of the 3 NTMs were identified as M. intracellulare and both were subjects that had had a history of TB treatment. While the rate of MDR TB appears lower than might be expected in a tertiary hospital, 80% of subjects enrolled in the study have never been treated for TB. In addition, the hospital staff reported that most of their previously treated patients were not eligible for the study due to the limited time allowed on anti-tuberculosis medications prior to enrollment. Half of the confirmed MDR TB cases occurred in subjects who were treatment nave, suggesting on-going primary transmission of MDR TB in this study population. The second protocol for this site is now in development and will build on the results of the metronidazole and linezolid studies from Korea. The protocol is titled Sirturo and Linezolid for Accelerated Management of MDR TB (SLAM TB) and the goals of this study are to estimate the efficacy and safety of an investigational 6-month treatment regimen for MDR TB and to explore whether imaging changes correlate with and therefore may predict efficacy. Because DS TB can be successfully treated with a potent, 6-month regimen, MDR TB (which currently takes about 2 years to treat) should also be successfully treated in 6 months if the drugs used are potent enough and sensitive. This study builds on the outcomes of our linezolid study, incorporating this drug as one of the backbone drugs in this investigational regimen. This study also builds on the results of the PET/CT analysis of the metronidazole study, expanding our data set to determine the predictive ability of PET/CT as a radiological biomarker (radiomarker) of future treatment outcomes at an early time point. There is currently no good biomarker to predict treatment outcomes early in therapy. For drug sensitive pulmonary TB, the biomarker with the most experience to predict non-relapsing cure is sputum culture conversion at 2 months. Even this biomarker, however, predicts poorly with one study noting 2-month culture positivity independently predicting relapse (HR 2.8, 95% CI 1.7-4.7) but with a positive predictive value of only 18% and sensitivity only 50%. The data for MDR-TB patients are even less certain. Thus, MDR TB patients are left to take a long and complex treatment regimen with no clear early predictor of cure. If a sensitive marker to predict treatment success or failure could be identified early in treatment, this could potentially have a major impact on TB clinical trials by serving as an early surrogate endpoint for treatment outcomes in drug trials, significantly reducing the time to licensure. In addition, patients on routine treatment can be assessed early for treatment outcomes, allowing additional targeted interventions for those predicted to do poorly. A study of the investigational treatment regimen planned to be used in SLAM TB is currently being done in marmosets and, if successful, this protocol is expected to open in both Korea and China in the coming year.